The positive charge of the imidazole side chain of histidine7 is crucial for GLP-1 action.
Glucagon-like peptide-1(7-36)amide/(7-37) (GLP-1) is an incretin hormone which plays an important role in postprandial glucose homeostasis. Since GLP-1 potentiates glucose-induced insulin secretion, stimulates insulin biosynthesis and inhibits glucagon release, it is a potential tool for the treatment of diabetes mellitus. For this, an exact understanding of the structural/functional moieties of the peptide is mandatory. The present study investigates the importance of structural features of histidine7 at the N-terminus for GLP-1 action. Based upon binding and activity data obtained from ten different GLP-1 analogues we show that not the positive charge of the free alpha-amino group but the positive charge of the imidazole side chain of histidine is crucial for GLP-1 action. The presence of a ring structure and a basic function as well as the correct positioning of both seems to be decisive.
Hareter
A
A
Clinical Research Unit for Gastrointestinal Endocrinology, Philipps-University of Marburg, Germany.
Hoffmann
E
E
Bode
H P
HP
Göke
B
B
Göke
R
R
D000818:Animals; D001667:Binding, Competitive; D006224:Cricetinae; D018076:DNA, Complementary / Q000235:genetics; D005934:Glucagon / Q000737:chemistry* / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1; D000067757:Glucagon-Like Peptide-1 Receptor; D006639:Histidine / Q000737:chemistry*; D007093:Imidazoles / Q000737:chemistry* / Q000276:immunology; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism*; D011498:Protein Precursors / Q000737:chemistry* / Q000378:metabolism*; D051381:Rats; D018027:Receptors, Glucagon / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection / Q000235:genetics
D018076:DNA, Complementary; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D007093:Imidazoles; D010446:Peptide Fragments; D011498:Protein Precursors; D018027:Receptors, Glucagon; D006639:Histidine; C029899:imidazole; D052216:Glucagon-Like Peptide 1; D005934:Glucagon